Chloromethylsulfonamides of cyclic diamines



CAHIVHIY C 3,203,952 Patented Aug. 31, 1965 3 203 952 The novelcompounds of the invention are prepared by tin hl than 1 d 'th l'ccmonoismrnYrsuirdi i aMmns or CYCLIC 23 ch 6 3 DIAML S Leo A. Paquette,Portage Township, Kalamazoo County,

Mich assignor to The Upjohn Company, Kalamazoo, )CHDm Mich., acorporation of Delaware No Drawing. and Dec. 3, 1962, Szer. 'No. 242,073h 10' aims. .260- 39) wherein m and n are 2 or 3 and R is a saturatedhydro- This invention relates to novel compositions of matter 10 carbondi of not more than 10 carbon atoms, R and to a process for theirpreparation and 18 part cularly for example, can be alkyl, Such asmethyl, ethyl, propyl, directed to chloromethylsulfonamides of cyclicdiammes l, pentyl, hexyl, heptyl, octyl, Bony], and decyl, and and tothen P P the isomeric forms thereof; cycloalkyl, such as cyclo I Thenovel compounds of the invention have the followpropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2. mg formula: cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclo- (CH) decyl, bornyl, fenchyl,cyclopentylpropyl, and the like;

aralkyl such as benzyl, phenethyl, S-phenylpropyl, 4- ClCHzSOz- NRphenylbutyl, a-methylbenzyl, a-ethylbenzyl, p-isopropyl- 0H, 1 benzyl,and the like; aryl, such as phenyl, tolyl (o-, m-, 20 and p-), xylyl(all isomers), isopropylphenyl (0-, m-, and

p-) land Z-naphthyl, and the like. wherein m and n are 2 or 3 and R is asaturated hydro- The reaction advantageously is carried out in theprescarbon radical of not more than 10 carbon atoms, for ence of aninert solvent and an acid binding agent for example, alkyl, cycloalkyl,aralkyl, and aryl. They have reaction with the hydrogen chlorideliberated during the analgesic activity and are useful in producinganalgesia reaction. An ences of the cyclic diamine can be used inmammals, poultry, and like animals when adminisas the acid bindingagent; alternatively there can be used tered oralla or pzgienterglly.Thea! alsc;ll have antifimggll flor tlgis purpttisst an inorganic lLasesuchha? sodium hNyactivity an can use as an in ustri or agricu tur I'OXle or a e iary amine suc as triet y amine or fungicide. methylpiperidine.Advantageously the inert solvent is The novel compounds of the inventionare nitrogenous an aprotic solvent, for example, a chlorinatedhydrocarbases and as such can exist in both the protonated and n l n cha h f m. m yl chloride, nonprotgrgated form accorlirig to the plljl oftle eivirog; g g z t llld chloroieliiifieneik Hyidroxglic sglventsiment. e nonprotonate orm can e oxi ize wi Wa r, me m an e a ano s an ace1c aci hydrogen peroxide for example, to form the N-oxide, and likeacids, can be lJSed but are 1685 desirable because The N-oxide also canexist in both the protonated and of the d1fiiculty of isolating theproduct from the reacnonprotolrfted form ac;o;ding to thebpl-l 0g thelenviron; g wfig ig t pp g 2 gl rysfriim aboutt O; ment. e protonate ormscan e iso ate as aci 8 8391011 lmes 6 g P 0 addition salts which areuseful for upgrading the free base 5 2, sollaentg g y fl g between abqutand free base N-oxide forms, i.e., the nonprotonated l 011 001112 0 i ereaction mixforms. Suitable acids for this purpose include hydro- 40lmtlally y be desirable to avoid ex e eatchloric acid, sulfuric acid,phosphoric acid, acetic acid, 8- succinic acid, salicylic acid, maleicacid, thiocyanic acid, The mvcntlon 9 3' be more fully understood yffiferfiuosilicic acid, picric acid, Reineckes acid, azobenzenewoe tothe followms examplessulfonic acid, and the like. The acid addition saltcan GENERAL PROCEDURE -E g neutrali-ngg free Equimolar quantities ofchloromethanesulfonyl chlo ase W1 e appropria act or y me a esis. Thenovel chloromethylsulfonamides (Formula I) are 'gj fifigg g i g ggi gg gg g gg :5: aiiifiii iifiaiiiilifi dogma was me a aldehyde according toUS. Patents 2,424,320 and 2, 06 s fi i f fi fa gg i $3 144 are useful asicklin inhibitors, and the fluosilicic p c 6 i m c om acid additionsalts are useful as motEproofing agents acz t g eep the tempera?"cording to Us. Patents 1,915,334 and 2,075,359. was g i g g g i g ggiffs E The novel compounds of the m-vemlon can also exlst form was removedby distillation at reduced pressure or in the form of quaternary ammomumsalts, such for exb d d th d ample, as those obtained by coordinatingthe free base i a an 1 e was cryst me from a form with an alkyl halide,for example, methyl, ethyl, Sm C so van or so vent sys P PYL blltyl, P yheXyl, P y i y decyl, Y i Example1,-1-(chloromethylsulfonyl)-4-methylpipertetradecyl, and octadecylchlorides, bromides, and iodides, azine hydrochloride including theisomers thereof. The quaternary ammonium salts are useful for formingthe corresponding clcjmso pf 4311,1191 quaftelmary amrliioniufi?1 saltsof fluolsgicic acid itlti'hich at; F 10 O (0 10 kf/ h 1 use u as motproo g agents. ese uos cic act rom g. mo e o N-met y piperazine andsalts can be formed by metathesis with an inorganic find 14.9 g. (0.10mole) of chloromethanesulfonyl chloride silicate or by forming thequaternary ammonium hythere was obtained, after evaporation of thechlorofrom, droxide (by treating the salt with an equivalent of base, apale yellow gummy solid. Crystallization of this mae.g., sodiumhydroxide) and neutralizing it with fluosilicic terial frommethanol-ether gave 15.5 g. (62.3 percent) of acid. The hi her alkylquaternary ammonium salts, i.e., product, M.P. 182l90 C. (dec.). Fourrecrystallizathose containing from 8 to 18 carbon atoms, inclusive,tions of this material from methanol gave pure l-(chloroin the alkylgroup, are useful as cationic surface active agents and disinfectants.

methylsulfonyl)-4-methyl-piperazine hydrochloride white stars, M.P. 205C. (dec.).

3 Analysis.-Calcd. for C H Cl- N O S: C, 28.92; H, 5.66; Cl, 28.46.Found: C, 29.14; H, 5.69; Cl, 28.76.

Example 2.-1 -(chloromethylsulfonyl) hexahydro-4- mehyI-1,4-diazepinehydrochloride cwmso-N N-CHrHCl From 11.4 g. (0.10 mole) ofN-methylhomopiperazine and 14.9 g. (0.10 mole) of chloromethanesulfonylchloride there was obtained, after decantation of the chloroform, agummy, pale orange solid. Crystallization of this material from methanolafforded 17.6 g. (67.0 percent) of pale yellow crystals, MP. 172175 C.Two recrystallizations of this material from methanol-ether gave pure1-(chloromethylsulfonyl)hexahydro-4-mehyl-1,4-diazepine hydrochloride aswhite stars, M.P. 178180 C.

AnaIysis.-Calcd. C H Cl N O S: C, 31.94; H, 6.13; Cl, 26.94. Found: C,31.91; H, 6.11; Cl, 27.17.

Example 3.-1-(chloromethylsulfonyl) octahydro-S- methyl-1,5-diazocinehydrochloride CICHIS O3-N Nl CHPHC1 From 9.3 g. (0.0726 mole) of1-methyl-1,5-diazacyclooctane and 10.8 g. (0.0726 mole) ofchloromethanesulfonyl chloride there was obtained, after evaporation ofthe chloroform, a colorless gum. Crystallization of this material fromisopropanol gave 15.6 g. (77.6 percent) of white solid. Threerecrystallizations of this material from aqueous isopropanol gave purel-(chloromethylsulfonyl octahydro-S -methyl-1 ,S-diazocine hydrochlorideas an amorphous white solid, M.P. 207-209 C. (dec.).

Analysis.-Calcd. for CaHmClgNgOgSi C, H, 6.54; N, 10.11. Found: C,34.32; H, 6.65; N, 9.65.

The free bases corresponding to the above examples are obtained byneutralization of the hydrochlorides with a strong base, such as sodiumhydroxide or a quaternary ammonium base exchange resin, or by metathesiswith silver carbonate. The N-oxides are formed by oxidizing the freebases with a peroxide, for example, hydrogen peroxide.

By substituting the N-methyl cyclic diamines of the examples by thecorresponding N-R cyclic diamines where R is any of the saturatedhydrocarbon radicals exemplified above, there are obtained thecorresponding chloromethylsulfonamides.

4 I claim: 1. A member of the group consisting of a compound of theformula:

alm ClClEhSOg-N /NR (CI-1a).. (I)

wherein m and n are integers of from 2 to 3 and R is bydrocarbon free ofolefinic and acetylenic unsaturation of not more than 10 carbon atomsand the acid addition salts, the alkyl quaternary ammonium salts whereinthe alkyl has not more than 18 carbon atoms, and the N- oxides thereof.

2. l-(chloromethylsulfonyl)-4-methylpiperazine.

3. 1 (chloromethylsulfonyl)hexahydro-4-methyl-1,4- diazepine.

4. 1 (chloromethylsulfonyl)octahydro-5-methyl-l,5- diazocine.

5. 1 (chloromethylsulfonyl)-4-methylpiperazine hydrochloride.

6. l (chloromethylsulfonyl)hexahydro-4-methyl-1,4- diazepinehydrochloride.

7. 1 (chloromethylsulfonyl)octahydro-5-methyl-l,5- diazocinehydrochloride.

8. A compound of Formula I wherein m and n are integers of from 2 to 3and R is a hydrocarbon radical of not more than 10 carbon atoms selectedfrom the group consisting of alkyl, cycloalkyl, aralkyl, and aryl.

9. A compound of Formula I wherein m and n are integers of from 2 to 3and R is alkyl of not more than 10 carbon atoms.

10. A compound of Formula I wherein m and n are integers of from 2 to 3and R is methyl.

References Cited by the Examiner UNITED STATES PATENTS 2,507,408 5/50Jacob 260-268 3,041,341 6/62 Barrett et a1 260-268 3,098,066 7/63 Mull260-239 OTHER REFERENCES Burger: Medicinal Chemistry (New York, 1960),pages 81, 43, and 1055.

Culvenor: Rev. Pure App. Chem., vol. 3, pages 83- 114 (1953).

NICHOLAS S. RIZZO, Primary Examiner.

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: